Mifepristone is a synthetic  19-nor steroid compound with a bulky p-(dimethylamino)phenyl substituent above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor conformation and a hydrophobic 1-propynyl substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor binding affinity.

 

 

It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency  contraceptive.

In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist).

Mifepristone is also a powerful glucocorticoid receptor antagonist and a weak androgen receptor antagonist  and has occasionally been used in refractory Cushing’s Syndrome (due to ectopic/ neoplastic ACTH/Cortisol secretion).

Mifepristone’s relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol; its relative binding affinity at the androgen receptor is less than one third that of testosterone. It does not bind to the estrogen receptor or the mineralocorticoid receptor.

PHARMACOLOGY

Pharmacodynamics

The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites.Mifepristone inhibits the activity of endogenous or exogenous progesterone leading to  termination of pregnancy .

Doses of 1 mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins.

Mifepristone also exhibits  antiglucocorticoid and weak antiandrogenic activity. Doses of 4.5 mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol.

Pharmacokinetics

Absorption

Following oral administration mifepristone is rapidly absorbed, with a peak  plasma concentration  occurring approximately 90 minutes after ingestion.

Distribution

Mifepristone is 98% bound to plasma proteins, albumin and alpha 1 -acid glycoprotein. Binding to the latter protein is saturable, and the drug displays nonlinear kinetics with respect to plasma concentration and clearance.

Following a distribution phase, elimination of mifepristone is slow at first (50% eliminated between 12 and 72 hours) and then becomes more rapid with a terminal elimination half-life of 18 hours.

Metabolism

Metabolism of mifepristone is primarily via pathways involving N-demethylation and terminal hydroxylation of the 17-propynyl chain.                                                                                                                                                                      CYP450 3A4 is primarily responsible for the metabolism. The three major metabolites identified in humans are:

(1) N- monodemethylated metabolite most widely found in plasma,

(2) Results  from the loss of two methyl groups from the 4-dimethylaminophenyl in position 11ß  and

(3) Results from terminal hydroxylation of the 17-propynyl chain.

Excretion

83% of the drug is excreted  by the faeces and 9% by the urine. Serum levels are undetectable

Indications

1. Medical termination of intrauterine pregnancies of up to 49 days gestation

2. Softening and dilatation of the cervix prior to mechanical cervical dilatation for pregnancy termination

3. Labor induction in fetal death in utero.

4. Regular long-term use as an oral contraceptive

5.To treat Endogenous Cushing’s syndrome –Recently FDA approved

 

Undesirable effects

Women typically experience abdominal pain, including uterine cramping and vaginal bleeding or spotting.

Other commonly reported side effects are nausea, vomiting and diarrhoea. Pelvic pain, fainting, headache, dizziness ,fever and asthenia occurred rarely.

Serious bacterial infection, bleeding, ectopic pregnancies that have ruptured and death  including another death from sepsis were recently reported

 

Drug Interactions 

Although specific drug or food interactions with mifepristone have not been studied, on the basis of drug`s metabolism by CYP 3A4, it is possible that

-Ketoconazole, Itraconazole, Erythromycin, and grapefruit juice may inhibit mifepristone  metabolism (increasing serum levels of it).

-Rifampin, Dexamethasone, , and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine)   may induce mifepristone metabolism (lowering serum levels of mifepristone).

-Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anaesthesia.

 

 Contraindications

Contraindicated in patients with any one of the following conditions:

-Confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass

- IUD in place

-Chronic adrenal failure

-History of allergy to mifepristone

-Haemorrhagic disorders

-Inherited porphyria

-Anticoagulant or long-term corticosteroid therapy